Elucidating the mechanisms underlying compensation, or changes in smoking behavior that occur in response to decreased nicotine availability, is crucial for characterizing smoking reduction as an approach to managing tobacco dependence in smokers who are unwilling or unable to quit. Our laboratory has developed two rodent models of smoking reduction in which compensatory increases in nicotine selfadministration are observed following reductions in duration of daily nicotine access or nicotine dose per infusion. The current proposal will examine whether severity of the negative affective (i.e., emotional) consequences of nicotine withdrawal, as assessed by elevated intracranial self-stimulation thresholds, is predictive of compensation in either the dose or access models of reduction. Additional studies will examine whether passive immunization with a nicotine-specific monoclonal antibody, which decreases nicotine distribution to the brain and prolongs the drug's half-life, is effective in reducing compensation. Characterizing predictors and treatments for compensation may facilitate the use of smoking reduction for the treatment of nicotine addiction, and may also lead to a better understanding of the mechanisms regulating smoking behavior. Relevance to public health: Cigarette smoking is the leading preventable cause of death and disease in the modern world. Although reducing smoking may decrease the harmful effects of cigarettes, the effectiveness of this strategy may be limited by compensatory changes in smoking behavior (for example, increasing the depth of each puff) that occur following smoking reduction. The proposed studies, which will attempt to characterize predisposing factors and a possible treatment for compensation using two animal models of smoking reduction, will provide insights into how to limit this behavior and better understand the potential role of smoking reduction as an approach towards managing tobacco dependence. [unreadable] [unreadable] [unreadable]